Mazen Al-Obaidi: Kisspeptin and the Neuroendocrine Control of Ovulation

“Kisspeptin, a brain chemical that sets the moment of ovulation, is now being examined as a fertility treatment.

Nerve cells in the hypothalamus release it, and it tells the brain when to fire the hormone signal that frees an egg from the ovary. Last year a team at Imperial College London reported the first nasal spray version tested in people, a route that avoids injection (Mills et al., 2025). Doctors have already used the injected form to mature eggs during in vitro fertilisation (IVF), and the same pathway is now being studied in women whose periods have stopped, and in polycystic ovary syndrome, where the signal runs too fast.

The sequence is short:

• Kisspeptin cells in the brain fire in a constant rhythm.
• Gonadotropin-releasing hormone (GnRH) is released in short bursts that follow that rhythm.
• The pituitary gland then releases the hormones LH and FSH.
• The ovary grows a follicle, and a burst of LH releases the egg.

As a scientist, I find the speed of this shift striking: a receptor discovered through rare genetic cases is now in the hands of fertility clinicians. My own expectation is that the first real use of the nasal route sits in IVF triggering rather than in FHA, because a single timed dose is a far easier problem than a schedule sustained over weeks.

What does kisspeptin do in the brain?

Kisspeptin cells sit next to the cells that release GnRH and set their rhythm. Two groups of them matter most.

• The arcuate group lies deep in the hypothalamus and keeps the beat, which is why researchers call it the pulse generator.
• The front group reacts to oestrogen from the ovary and creates the large burst of activity just before ovulation.
• Around mid-cycle, the leading follicle floods the bloodstream with oestrogen, and the brain amplifies hormone release instead of holding it back.
• Kisspeptin increases, GnRH increases, and the pituitary fires the large burst of LH that opens the follicle and releases the egg.
• Children born with a faulty kisspeptin receptor never enter puberty at all (Skorupskaite et al., 2014).

In IVF, clinicians purposely switch off that natural burst and replace it with an injection, and this is the point where a kisspeptin trigger enters.

What happens when the kisspeptin signal runs too slow or too fast?

The same pathway fails in two opposite ways.

• In Functional Hypothalamic Amenorrhoea (FHA), periods stop even though nothing is wrong with the ovary or the womb.
• Low food intake, weight loss, hard training and stress slow the brain signal until LH bursts become rare or stop.
• Kisspeptin given through a drip to five women with FHA raised the bursts from 1.6 to 5.0 over eight hours (Jayasena et al., 2014).
• No single dose suited everyone, and a high dose given without a break made the brain stop responding.
• In polycystic ovary syndrome, the bursts come too often, LH stays high, and the balance between LH and FSH is lost, which stops a follicle maturing properly.
• A drug that blocks the receptor for neurokinin B decreased LH secretion and reduced LH pulses in women with PCOS (Skorupskaite et al., 2020).

In my reading of these data, the obstacle is pharmacological rather than biological: the pathway responds, but the schedule that keeps it responding has not been worked out. I regard this balance as the most useful part of the story, because it treats ovulation as a rhythm to be tuned rather than a switch to be flipped.

Does kisspeptin mature eggs in IVF?

The clearest clinical test so far came at the Hammersmith Hospital unit in London (Abbara et al., 2015).

• A single kisspeptin injection was given to 60 women at high risk of Ovarian Hyperstimulation Syndrome (OHSS), a dangerous over-reaction of the ovaries to fertility drugs.
• Eggs matured in 95% of the women.
• 45% of embryo transfers produced a live birth.
• No woman developed moderate or severe OHSS.
• Kisspeptin works through the woman’s own brain cells, so the LH burst is shorter than the one caused by hCG and the ovaries are pushed for less time.
• The trial was small, ran in a single centre, and has still not been tested against the standard trigger in a large study.

Does kisspeptin have to be injected?

An injection is a barrier for any peptide drug, which is why the route of delivery has been studied (Mills et al., 2025).

• A nasal spray given to healthy men raised hormone levels quickly.
• The spray remained stable for up to 60 days in a fridge.
• In mice, the drug collected in the lining of the nose, and kisspeptin receptors turned up on nerve cells in the smell centre of the brain.
• At a 2025 endocrinology congress, the same group reported a smaller but earlier peak after the spray than after a drip.
• The study included men only, so women are the obvious next group.

Plenty is still missing:

• The dose needed in FHA varied from woman to woman, so a single fixed treatment does not suit every patient.
• Short repeated schedules have not been properly tested in women.
• In IVF, nobody yet knows which patients gain most from a kisspeptin trigger compared with the standard one.
• The nasal results are early and need repeating in women with fertility problems.

My own expectation is that the first real use of the nasal route sits in IVF triggering rather than in FHA, because a single timed dose is a far easier problem than a schedule sustained over weeks.”

Written by Mazen Al-Obaidi,

Assistant Professor, University of Technology and Applied Sciences

References:

Title: Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy

Authors: Ali Abbara, Channa N. Jayasena, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Gurjinder M. K. Nijher, Alexander N. Comninos, Deborah Peters, Adam Buckley, Risheka Ratnasabapathy, Julia K. Prague, Rehan Salim, Stuart A. Lavery, Stephen R. Bloom, Matyas Szigeti, Deborah A. Ashby, Geoffrey H. Trew, Waljit S. Dhillo

You can read the Full Article in The Journal of Clinical Endocrinology and Metabolism.

Title: Increasing LH Pulsatility in Women With Hypothalamic Amenorrhoea Using Intravenous Infusion of Kisspeptin-54 Get access Arrow

Authors: Channa N. Jayasena, Ali Abbara, Johannes D. Veldhuis, Alexander N. Comninos, Risheka Ratnasabapathy, Akila De Silva, Gurjinder M. K. Nijher, Zainab Ganiyu-Dada, Amrish Mehta, Catriona Todd, Mohammad A. Ghatei, Stephen R. Bloom, Waljit S. Dhillo

You can read the Full Article in The Journal of Clinical Endocrinology and Metabolism.

Title: Intranasal kisspeptin administration rapidly stimulates gonadotropin release in humans

Authors: Edouard G. Mills, Mauro S.B. Silva, Virginia Delli, Laurine Decoster, Gaetan Ternier, Jovanna Tsoutsouki, Layla Thurston, Maria Phylactou, Bijal Patel, Lisa Yang, Sophie A. Clarke, Megan Young, Emma C. Alexander, Sandhi Nyunt, Arthur C. Yeung, Muhammad Choudhury, Anastasia Newman, Paul Bech, Ali Abbara, Magda Swedrowska, Ben Forbes, Vincent Prévot, Konstantina Chachlaki, Paolo Giacobini, Alexander N. Comninos, Waljit S. Dhillo

You can read the Full Article in eBioMedicine.

Title: The kisspeptin-GnRH pathway in human reproductive health and disease

Authors: Karolina Skorupskaite, Jyothis T George, Richard A Anderson

You can read the Full Article in Human Reproduction Update.

Title: Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome

Authors: Karolina Skorupskaite, Jyothis T George, Johannes D Veldhuis, Robert P Millar, Richard A Anderson

You can read the Full Article in Human Reproduction.

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